Cisplatin

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Continuing Education Activity

Cisplatin is a medication used to manage and treat solid tumors and hematologic malignancies. It is in the alkylating agent class of cytotoxic medications. This activity reviews the indications, action, and contraindications for cisplatinum as a valuable agent in treating malignancy. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for the interprofessional oncology team members in the care of patients with malignancy treated with this agent.

Objectives:

  • Identify the mechanism of action of cisplatin.
  • Describe the adverse effects associated with cisplatin therapy.
  • Review the appropriate monitoring necessary with cisplatin therapy.
  • Outline how collaboration and coordination among the interprofessional team can enhance patient care when dosing and monitoring cisplatin to improve patient outcomes for patients receiving antineoplastic therapy with cisplatin.

Indications

Cisplatin is an antineoplastic agent that came into use in the late 1970s. Cisplatin, while highly toxic, is one of the most heavily utilized chemotherapeutic agents for hematologic and solid tumor malignancies. It can be used as a single-agent or combination therapy for induction and neoadjuvant therapy. 

Adult Indications

Cisplatin is FDA approved for the treatment of advanced ovarian cancer, testicular cancer, and bladder carcinoma.[1][2] However, clinicians frequently use cisplatin off-label for a number of other malignancies, as detailed below, when the benefits may outweigh the risks of adverse drug effects. 

Malignancies that predominate in women, such as breast cancer, cervical and endometrial carcinoma, and gestational trophoblastic neoplasia, sometimes receive treatment with cisplatin in combination with other medications such as taxane derivatives, 5-FU, and doxorubicin.[3][4][5] While hormone-sensitive and Her2neu-positive tumors may respond well to targeted therapy, cisplatin is also useful in treating triple-negative breast cancer as a single agent neoadjuvant therapy.[3]

Gastrointestinal malignancies such as esophageal, gastric, and hepatobiliary cancer have also been treated off-label with this medication and radiation.[6][7][8] Advanced cervical cancer is another off-label indication. Lung cancer, both small and non-small cells, can be treated off-label using etoposide and cisplatin combination therapy.[9][10]

Other off-label uses include treatment for metastatic, advanced, and refractory cancers; this includes the treatment of Hodgkin lymphoma, non-Hodgkin lymphoma, penile cancer, thymoma, head and neck cancers, osteosarcoma, multiple myeloma, and mesothelioma.[11][12][13]

Pediatric Indications

Cisplatin has no approved indications for treatment in children. When utilized off-label, its indications are for historically aggressive tumors.[14][15] It is sometimes useful in treating germ cell tumors, hepatoblastoma, medulloblastoma, neuroblastoma, and osteosarcoma, but universal guidelines on dosing and duration are not available.[16][17][18]

Mechanism of Action

Cisplatin acts via non-cell cycle-specific cytotoxicity, which is achieved through the covalent binding of platinum to the purine bases guanine and adenine. This covalent binding leads to intra-strand and inter-strand crosslinks causing subsequent strand breaks. While DNA repair mechanisms are at play, cells often undergo apoptotic or non-apoptotic cell death due to remnant damaged DNA, RNA, and proteins.[19] Cisplatin chemotherapy is particularly effective at targeting rapidly dividing cells, as appreciated in rapidly growing malignant tumors.[20] Theoretically, cisplatin may not be as useful for slow-growing tumors.

The drug is primarily excreted in the urine, with 10% in the bile. Its initial half-life is approximately 20 to 30 minutes, with a terminal half-life of 24 hours. ALbumin-bound platinum undergoes slow administration of minimally five days.

Administration

Cisplatin can be administered as an injectable agent both intravenously and as an intra-arterial agent.[21] Cisplatin can also be utilized as an intraperitoneal agent, as seen in treating carcinomatosis and primary peritoneal carcinoma. However, this use is not FDA approved and is “off-label” use.[22] Before administration, the patient must achieve adequate hydration and maintain hydration and urinary output 24 hours after administration. Anti-emetic agents can be utilized prophylactically to prevent nausea and vomiting.[23]

Approved Adult Dosing Regimens

  • Advanced testicular cancer: 20 mg.m^2 IV for a single dose on day 1 of a 21 or 28-day cycle; maximum 100 mg/m^2 per cycle.
  • Advanced bladder cancer: 50 to 70 mg.m^2 IV for a single dose on day 1 of a 21 or 28-day cycle; maximum 100 mg/m^2 per cycle.
  • Advanced ovarian cancer: 100 mg.m^2 IV for a single dose on day 1 of a 21 or 28-day cycle; maximum 100 mg/m^2 per cycle.

Cisplatin can be used as monotherapy or as part of a multi-drug regimen. Patients should have proper hydration while monitoring urine output before, during, and for 24 hours following administration.

Renal Dose Adjustments

  • Creatinine clearance between 10 and 50: decrease dose by 25%
  • Creatinine clearance below 10: decrease dose by 50%
  • Hemodialysis: Decrease the dose by 50% with no supplement; administer after dialysis on dialysis days with no supplement
  • Peritoneal dialysis: Decrease the dose by 50% with no supplement

Adverse Effects

Extravasation - If extravasation is suspected, the infusion should stop immediately. Any obvious fluid collection should be aspirated, and the extremity elevated. The antidote, sodium thiosulfate, should be administered.[24]

Secondary malignancy - Leukemia is the most common secondary malignancy after treatment with cisplatin, and this typically occurs many years after completion of treatment.[25][26]

Tumor lysis syndrome can occur after treatment with many chemotherapeutic agents and manifest as hyperuricemia, alteration in hemodynamics, hyperkalemia, and azotemia. Uric acid-reducing treatments may be necessary.[25][27]

Common Side Effects[27]

  • Mild nausea
  • Vomiting 
  • Diarrhea
  • Temporary hair loss
  • Loss in the ability to taste food
  • Hiccups
  • Dry mouth
  • Dark urine
  • Decreased sweating
  • Dry skin
  • Dehydration

Drug Interactions

Caution is necessary when administering cisplatin with any of the following medications. Most drug interactions result in cumulative and dose-dependent hematologic, renal, and neurotoxic effects. Due to cumulative myelosuppression, cisplatin should also not be used concurrently with immunosuppressive medications.[28][29] 

  • Alpha-lipoic acid
  • Aminoglycosides
  • Baricitinib
  • BCG
  • Chloramphenicol
  • Clozapine
  • Deferiprone
  • Denosumab
  • Dipyrone
  • Echinacea
  • Fosphenytoin
  • Leflunomide
  • Lenogristim
  • Lipefilgrastim
  • Natalizumab
  • Nivolumab
  • Ocrelizumab
  • Palifermin
  • Pidotimod
  • Pimecrolimus
  • Promazine
  • Roflumilast
  • Siponimod
  • Sipuleleucel-T
  • Tacrolimus
  • Taxane derivatives
  • Tertomotide
  • Topotecan
  • Trastuzumab
  • Vaccinations
  • Vinorelbine

Contraindications

There are few absolute contraindications for cisplatin use for the treatment of malignancies. Severe hypersensitivity to cisplatin or platinum compounds would preclude its administration; cisplatin is contraindicated in patients who have had severe hypersensitivity reactions, and rechallenge is not a recommendation.

Cisplatin has been shown to cross the placenta and may cause fetal harm.[30][31] Women of reproductive age should use reliable contraception during treatment and up to a year from the final treatment date. Cisplatin is also present in the breastmilk of lactating women on a cisplatin regimen.[32] Breastfeeding is not recommended during treatment.[32] If hypersensitivity occurs, the provider should discontinue cisplatin immediately.[33] 

Monitoring

A pregnancy test is necessary to determine pregnancy status in female patients before administering cisplatin.[30]

Hematologic - The clinician should order a complete blood count (CBC) before initiating treatment and before each subsequent treatment course.[25]

Renal function - Serum creatinine, blood urea nitrogen, creatinine clearance, and electrolytes (Na, K, Ca, Mg) require an assessment before treatment administration.[34][35]

Hearing and vestibular - Audiometric testing should be ordered in pediatric patients to determine baseline and before each administration. After discontinuing therapy, audiometric testing should continue for several years.[25][35][36]

Infusion - The infusion site should be assessed before, during, and after drug administration to assess for infection and extravasation. The patient should be monitored clinically for complications of administration.[24][37][38]

One also has to monitor the patient for neuropathy, ocular changes, and signs of systemic infection.

Toxicity

CIsplatin has several black box warnings, including nephrotoxicity, peripheral neuropathy, severe nausea and vomiting, and myelosupression.

Gastrointestinal toxicity - Nausea and vomiting are dose-related side effects that can be severe and lead to metabolic derangements; this can persist for up to 1 week after administration. The strong recommendation is for prophylactic treatment with antiemetic agents.[39][25]

Myelosuppression - The chief concern with myelosuppression secondary to cisplatin use is the morbidity and mortality associated with infection. Monitor CBC and frequently assess for signs of infection. High clinical suspicion is necessary for infection and warrants a full workup.[25] Hematologic toxicity may require total treatment interruption. Often it will require dose modification if treatment is to continue.[25]

Neurotoxicity - Cisplatin is a dose-dependent neurotoxin.[40] Dose-related neurotoxicity most commonly manifests as peripheral neuropathy. This neuropathy may progress after discontinuation and, in some cases, might be irreversible.[25][41] While dosage may require alteration in the face of neuropathy, high-grade peripheral neuropathy may require total treatment discontinuation. 

Nephrotoxicity - Severe renal toxicity, including acute renal failure, may occur with Cisplatin administration. These effects are cumulative and dose-related. Pretreatment hydration plays a significant role in preventing renal toxicity.[25][34][35] The dose of cisplatin may require adjustment based on renal function with close monitoring of the glomerular filtration rate (GFR).[33]

Ocular toxicity/retinopathy - These adverse effects can manifest in a variety of ways, from loss of color discrimination to cortical blindness. Improvement usually occurs after discontinuation of cisplatin, and in some cases, total recovery may be possible.[25][42]

Ototoxicity - Monitoring for ototoxicity includes assessing the patient for ringing in the ears, high-frequency hearing loss, and decreased ability to follow conversations. Deafness has been reported but is not a common effect of cisplatin use. Loss of hearing acuity can be detrimental to language development in pediatric populations.[25][35]

Gonadotoxicity - Cisplatin is toxic to the gonads; it can cause impairment of spermatogenesis and dose-dependent ovarian failure leading to premature menopause.[25]

Enhancing Healthcare Team Outcomes

Interprofessional collaboration and care coordination between physicians (particularly oncology specialists), mid-level practitioners, nursing staff, pharmacists, and other healthcare providers enhance team performance and patient outcomes.[43] Working as a team while caring for patients undergoing treatment with cisplatin is of great importance.[44] As a team, monitoring for side effects and toxicity can be more efficient with fewer poor outcomes and earlier intervention.[45][44] 

Communication among healthcare professionals between various clinical disciplines is crucial. For example, any dose greater than 100 mg/m^2 for a single treatment course requires verification with the initial medication prescriber. The oncology specialty-trained pharmacist should also monitor for the extensive drug-drug interactions with cisplatin and promptly alert the ordering clinician upon finding any reason for concern.

Nurses need to be aware of the importance of hydration and monitoring the site of IV infusion for extravasation. Also, all clinicians should monitor the patient for signs of infection, renal impairment, and the development of tumor lysis syndrome. Open communication between the interprofessional team is vital to prevent the adverse effects of this agent while optimizing its therapeutic effect, driving optimal patient outcomes. [Level 5]

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Joann M. Gold

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Avais Raja

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